How is Biochemical Recurrence (BCR) after Radiation Therapy (RT) defined?

Biochemical Recurrence (BCR) Definition After Radiation Therapy

Biochemical recurrence after radiation therapy is defined as a PSA rise of 2 ng/mL or more above the nadir PSA, known as the Phoenix definition, which is the current standard established by the American Society for Radiation Oncology (ASTRO) and the Radiation Therapy Oncology Group. 1, 2

The Phoenix Definition (Current Standard)

• The date of failure should be determined "at call" (when the PSA threshold is reached) and not backdated, which was a major improvement over the older ASTRO definition 1
• The nadir PSA is defined as the lowest PSA value achieved after radiation therapy, which may take 18 to 30 months to reach 1
• This definition applies to external beam radiation therapy (EBRT) with or without neoadjuvant androgen deprivation therapy (ADT) 1

Historical Context: The Original ASTRO Definition

• The older ASTRO definition required 3 consecutive PSA increases after nadir, with the date of failure backdated to the midpoint between the nadir and the first of 3 consecutive rises 1
• This original definition had significant shortcomings: it failed to specify time intervals between PSA measurements, required backdating which artificially inflated success rates, and did not use PSA nadir as a risk factor 1
• Despite these limitations, the ASTRO definition (or variations thereof) was the most commonly used definition in 70 studies reviewed in 2007 1

Critical Differences from Post-Prostatectomy BCR

• After radical prostatectomy, BCR is defined as PSA ≥0.2 ng/mL with a second confirmatory level ≥0.2 ng/mL 2
• The radiation therapy definition differs fundamentally because RT does not eliminate all prostatic epithelium, so PSA may not become undetectable and residual functioning epithelium can produce PSA 1
• PSA levels after RT may take 2 to 3 years to reach nadir, unlike the 6-week washout period expected after surgery 1

Variability in Historical Definitions

The 2007 AUA guideline review identified 99 different definitions of BCR after radiation therapy in the published literature, demonstrating massive inconsistency 1. Common variations included:

• 2 consecutive PSA increases (15 studies) 1
• 3 consecutive PSA increases (9 studies) 1
• Various absolute PSA thresholds ranging from >0.1 ng/mL to >4.0 ng/mL 1
• Different criteria for PSA rises above nadir (ranging from 1.0 to 1.5 ng/mL increases) 1

Current Guideline Recommendations

• The AUA Panel recommends using the ASTRO criteria (now updated to the Phoenix definition) for patients treated with radiation therapy 1
• The NCCN guidelines define BCR after RT as "nadir PSA plus 2 ng/mL" 2, 3
• The ACR Appropriateness Criteria specifically cite the 2005 Phoenix Consensus Conference definition of "a rise by 2 ng/mL or more above the nadir PSA" 1

Emerging Challenges to the Phoenix Definition

• Recent evidence suggests the Phoenix criteria may be inadequate in the era of PSMA PET imaging, which can detect recurrent disease at PSA levels well below the 2 ng/mL threshold 4
• PSA kinetics (nadir levels and doubling time) provide superior prognostic information compared to static PSA thresholds 4
• Modern imaging techniques allow detection of recurrence earlier than the Phoenix threshold would indicate, potentially enabling earlier salvage interventions 4

Common Pitfalls to Avoid

• Do not use the outdated ASTRO definition with backdating, as this artificially inflates success rates and complicates outcome reporting 1
• Do not apply the post-prostatectomy BCR definition (PSA ≥0.2 ng/mL) to radiation therapy patients, as the biological context is completely different 1
• Do not expect PSA to become undetectable after RT, as residual benign prostatic tissue will continue producing PSA 1
• Be aware that the Phoenix definition may delay identification of recurrence in the modern PSMA PET era, where disease can be detected at lower PSA levels 4